Basic and clinical research by our team and others suggests intravenous glucose, insulin, and potassium (GIK)I metabolic myocardial support reduces ischemia-induced arrhythmias, progression from unstable angina pectoris I (UAP) to acute myocardial infarction (AMI), MI size, and mortality. Also, for ST elevation MI (STEMI), GIK may prolong time of benefit of coronary reperfusion. These effects should reduce short- and long-term mortality from acute coronary syndromes (ACS: including AMI and UAP) and the propensity for heart failure (HF). These benefits are related to the earliness of ACS, when both risk and opportunity to save lives are highest. Thus, we propose the IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) Trial, a randomized placebo-controlled clinical trial of immediate GIK as early as possible in ACS: in the prehospital emergency medical service (EMS) setting, or, for those presenting to emergency departments (EDs), immediately upon ED arrival. Distinct from prior and ongoing GIK trials, this will test GIK for all ACS rather than only for AMI (or STEMI), and its use in prehospital EMS and ED settings. Our primary hypothesis is that early GIK will reduce 30-day and 1-year mortality. Major secondary hypotheses posit GIK will reduce pre/in-hospital cardiac arrest, progression of UAP to AMI, and by this and limiting MI size, will reduce the propensity for HF. Other hypotheses address mechanisms of these effects. The project will take 5 years: a year preparing and testing operations, 28 months enrolling patients, and then completion of data collection, analysis, and reporting. Clinical sites will be in Massachusetts, Texas, and Wisconsin; this application is for trial coordination at Tufts-New England Medical Center (accompanying are 3: for Data Coordinating Center and 2 Core Laboratories). Inclusion of 15,450 patients (excluding AMI Killip class >2) should provide >=80% statistical power to detect 25% reductions in primary endpoints (30-day and 1-year mortality) and major secondary endpoints (cardiac arrest or mortality, and HF hospitalization or mortality, and progression of UAP to AMI). A 400-subject cohort assessed for LV function, ventricular arrhythmia markers, and biochemical tests, will provide >=80% power for clinically relevant differences between GIK and placebo. If the 30-50% reduction in acute mortality rates in prior GIK trials and reductions in HF are confirmed, this inexpensive treatment could substantially reduce the most common causes of death and hospitalization in the US.